Heart attack and related thrombotic diseases are among the leading causes of death in America. The American Heart Association estimates that as many as l.5 million people in the U.S. will suffer heart attacks this year, with more than one-third resulting in death. In addition, it is estimated that l/2 million Americans suffer a stroke per year with about 80 percent of all strokes caused by blood clots. Thrombosis, septic shock and a variety of related forms of diseases are associated with, and result from, the activation of one or more of the coagulation protease cascade pathways. In Phase I study, the investigators propose to develop a novel and general approach to the inhibition of serine proteinases based on the introduction, by site specific mutagenesis, of specific residues into the contact site of a common framework based on a prototypic Kunitz inhibitor. In the first application these residues will be chosen, based on molecular modeling and drug design principles, to impart potency and specificity towards coagulation factors VIIa and Xa. In Phase II study, they intend to develop therapeutic molecules based on the active inhibitors discovered in Phase I study. Additionally, in Phase II work, the strategy from Phase I research will be used to design specific inhibitors of other important serine proteases of the coagulation cascade, in particular, factors IXa, XIIa, XIa and kallikrein. The valuable information obtained in Phase I study relating three-dimensional structure with inhibitory activity will be used in Phase II work for the design of second generation, non-peptide therapeutics.